Adverse Drug Reactions to Anti-TB Drugs: Pharmacogenomics Perspective for Identification of Host Genetic Markers

Abstract

Adverse drug reactions (ADRs) are associated with clinical morbidity and, in severe cases, even mortality. Globally billions of dollars are spent on managing these ADRs for common and uncommon diseases. The developing world suffers from a high burden of tuberculosis, which requires 6-8 months of multi-drug treatment. In spite of most cases being treatable the problem persists mainly due to a high attrition rate associated with ADR mediated complications. Due to these reasons drug resistant strains have emerged and are now a serious challenge to TB eradication. To effectively deliver the available treatment regimen and ensure patient compliance it is important to manage ADRs more efficiently. Recent studies have demonstrated that drug outcomes are patient-specific and can, therefore be predicted. A few of these drugs, including a few administered for TB, have shown excellent correlation with response rates and development of ADRs. In this review, we profile information available in public domain for existing anti-TB drugs to understand the genesis of ADRs and patient response. Additionally, human genome variation databases have been used to correlate the frequency of these markers and their genomic variants in different populations.

Antituberculosis Drug‐Induced Adverse Events in the Liver, Kidneys, and Blood: Clinical Profiles and Pharmacogenetic Predictors

“…This variant could result in interindividual variability of CYP2D6 enzymatic activity or expression. Previous studies and our results suggest that the CYP2D6 gene may play a role in participating in the metabolism of ATDs or forming covalent adducts with ATDs, similar to the effect of some other general CYP enzymes on ATDs; however, this possibility should be verified in functional assays.…”

The Influence of Pharmacogenetic Variants in HIV/Tuberculosis Coinfected Patients in Uganda in the SOUTH Study

“…The first finding is somehow surprising because a less expressed OATP1B1 is associated with lower intrahepatic exposure of RIF. Because several studies demonstrate that liver injury is not linked to plasma exposure, our initial hypothesis was that alternative causes (such as hepatic or intracellular concentrations or specific metabolites) may link genetic variants to liver toxicity . On the contrary, PXR has been shown to modulate hepatotoxicity associated with RIF and INH cotherapy in a mouse model .…”

“…Because several studies demonstrate that liver injury is not linked to plasma exposure, our initial hypothesis was that alternative causes (such as hepatic or intracellular concentrations or specific metabolites) may link genetic variants to liver toxicity. 29 On the contrary, PXR has been shown to modulate hepatotoxicity associated with RIF and INH co therapy in a mouse model. 30 Although the exact mechanism has not been clarified, it may be related to the induction of CYPs (as shown by the presence of anti-INH, anti-CYP2E1, anti-CYP3A4, and anti-CYP2C9 antibodies) or through the PXR-mediated perturbation of heme biosynthesis.…”

Clinical features and risk factors for gout attacks during anti‐tuberculosis treatment: A case‐control study in South Korea

“…Compared to other side effects such as hepatotoxicity, pharmacogenetic factors prone to develop anti‐TB drug‐induced hyperuricemia and gout have not been investigated in depth. A recent review article has reported the high frequency of occurrence of single nucleotide polymorphisms of URAT1 gene in PZA‐related hyperuricemia, but their clinical relevance is as yet unclear . Further studies regarding the interactions between anti‐TB medications and certain genetic polymorphisms related to uric acid transport will be needed in the future.…”

“…9 Additionally, patients' genetic factors may influence the occurrence vance is as yet unclear. 23 Further studies regarding the interactions between anti-TB medications and certain genetic polymorphisms related to uric acid transport will be needed in the future.…”